Aqueous vitamin and mineral compositions



United States Patent AQUEOUS VITAMIN AND MINERAL COMPOSITIONS Clilford F. Gerber, New Hyde Park, and Oscar Klioze, Floral Park, N.Y.; said Gerber assignor to Chas. Pfizer & Co., Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed June 11, 1956, Ser. No. 590,790

Claims. (Cl. 167-81) This invention is concerned with aqueous vitamin and mineral compositions containing vitamin B ascorbic acid, and a pharmaceutically acceptable form of iron such as ferrous gluconate, ferrous sulfate, ferric ammonium citrate, peptonized iron, ferric glycerophosphate, and reduced iron. These substances are normally incompatible in aqueous preparations and heretofore have not been provided in a single composition of this type.

Vitamin B is a highly useful substance which has proven particularly necessary in the nutrition of animals including humans. However, this vitamin and the related compounds having vitamin B activity, that is vitamin B B E and other related substances are normally unstable and particularly when combined in solution with ascorbic acid or with iron-containing components. Furthermore, the decomposition of ascorbic acid is known to be catalyzed by metals including iron in various forms. This has been a troublesome problem in the art for some time since it is often highly desired to prepare multivitamin and mineral compositions containing each of these substances.

The preparation of such compositions has been possible to some extent, although not Without complications, in. the case of solid pharmaceutical preparations by effecting physical separation of the incompatible components. This has ordinarily been accomplished by coating the particles with inert materials, such as ethyl cellulose or magnesium stearate, but this has the disadvantage of reducing, in some instances, the physiological availability of the active components.

The incompatibility of ascorbic acid and iron with vitamin B active substances is particularly notorious in aque ous solution. This has militated against the preparation.

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loss and guar gum, and gelatin have a water binding capacity and are also useful components of the vehicles employed in the compositions of this invention. Sugar syrups which contain reducing sugars are not satisfactory for this use despite their water binding capacity. This is thought to be due to the incompatibility of the vitamin B active substances with the reducing sugars.

A preferred vehicle for the compositions. of the present invention comprises sorbitol of from about to 75% concentration. Sorbitol is a preferred vehicle for the above use, not only because of its high water solubility and its stabilizing effect on the vitamin B activity, but also because it has a sweet taste. Other polyols may of course be employed so long as they are pharmaceuti cally acceptable, have a high aqueous solubility, and have this water binding activity referred to above.

The lower polyols such as glycerol and propylene glycol alone are not suitable as vehicles for oral use because of their-poor taste and palatability and for parenteral use because of their irritating propensities. Polyols containing from about five to seven carbon atoms are in general preferred. The anhydropolyols such as the hexitans and hexides are also satisfactory. The most critical limitation on the selection of the polyol solvent is that it contain at least about five carbon atoms and that it contain no reducing group such as the aldehyde or ketone group. The

addition of soluble gums such as carboxymethyl cellulose or guar gum referred to above to the polyol vehicles appreciably assists in obtaining compositions having highly desirable properties in some instances. Ethanol can also be advantageously employed in the vehicle of this invention. In addition to its solvent power which makes it useful in the incorporation of other solutes, its use is also convenient for viscosity control.

To summarize then, the unique liquid vehicles of the i present compositions comprise a minor proportion of Water, up to about 30%, and from about 50 to 75% of a.

polyvol or an anhydro derivative thereof containing five j or more carbon atoms. Sorbitol and sorbitol containing minor proportions of glycerol, ethanol, propylene. glycol,

carboxymethyl cellulose, etc., are preferred vehicles. Ordinarily the maximum quantity of ethanol and/orlower polyol present is less than about half the volume of the final vehicle volume. When carboxymethyl cellulose is included as a component of the vehicle it is used in a very minor proportion, for example, less than about 5-10 of liquid compositions wherein these ingredients are pres- As a result of the present invention stable liquid com- 0 positions containing vitamin B active materials with ascorbic'acid and iron in various forms are provided by employing as a vehicle a liquid containing a minor proportion of water say up to about 30% and a major proportion of a polyol which in addition to being highly water soluble has a water binding capacity. The polyols arealiphatic hydrocarbon derivatives in which two or more carbon atoms bear hydroxyl groups. This waterbinding capacity is possessed by a variety of polyols such as glycerol, trimethylene glycol, propylene glycol, and the hexitols such as sorbitol which are derived from the hexosesby reduction. Gums such as .carboxymethyl cellumg./ml. Actually a vehicle comprising approximately 70% sorbitol and 30% water is satisfactory in most instances and the other components such as the lower polyols containing less than five carbon atoms, ethanol,

it and gums such as carboxymethyl cellulose are added only when they are needed to modify the physical properties of the vehicles such as viscosity, taste, palatability, and

solvent power in the particular preparation at hand. The f resulting compositions are viscous liquid preparations Qwhich may be administered readily to. patients to furnish a suitable dosage of vitamin B ascorbic acid, iron and other vitamins and minerals.

For preparations intended for oral use such as tonics,

hematinics, etc. 0.05-3 g. of ascorbic acid per fluid ounce has been found to be a convenient concentration range to employ. Similarly, 10-50 mcg. of vitamin B activity per ounce and about 10-150 mg. of iron in a suitable form, such as one of those listed above, per ounce of composition is suitable for oralformulations. Of course, the 1 amount of the iron compound employed will depend upon its solubility and the exact amount of iron contained therein. When ferrous gluconate serves as the iron-con-v taining ingredient, 50-600 mg./oz. is used. For parenteral use the above components are generally employed at the higher concentrations listed. Somewhat higher concen--'- Patented June 7, 196.0

, V 3 trations may be employed, but this is not normally necessary."

In addition to the compositions containing only vitamins and. minerals, otherspecific embodiments of this mem randum compositions containing therapeutic agents, such as hormones. In anti-inflammatory hormonev therapy, thej incorporation of vitamins and minerals including vitamin B ascorbic acid, and iron into oral preparations containing an anti-inflammatory steroid hormone, e.g. cortisone, hydrocortisone, prednisone, preduisolone, etc., hasv proven useful. Still further embodiments of this invention incorporating therapeutic components into nutritional supplements are geriatric preparationsor tonics which contain a variety of products included for their gonadotropic, metabolic, and anti-depressa'n't efiect. Therapeuticcomponents that have been used for thea-bove purposes include androgens and estrogens such as methyltestosterone and ethinylestradiol, thyroxme for its stimulating effect on anabolism, and amphetamine saltsfor'their stimulating effect on the central nervous system.

Specificexamples of various embodiments of the sort just describedappear hereinafter. While the compositions of, this, invention are usually administered orally,'they are suitable for parenteral use as well. One reason for the predominance of oral use is that they are ordinarily taken onya dailybasis by the patient at home. Oral administration of,course is preferred for this type of regimen. Parenteral administrtion is preferred in instances where nausea or extreme debility is involved. For maximum stabili y, the viscosities are preferably greater than about 100 centipoises. Compositions having viscosities in the range of about 100 to 400 centipoises are syringeable.

A preferred procedure for preparing the compositions of this invention involves dissolving the iron salt, for example ferrous gluconate, ferrous ammonium citrate or ferrous sulfate in the sorbitol at an elevated temperature say 70 to 100 C. Other components that are stable at the elevated temperature such as riboflavin and niacin amide are then dissolved and then the mixture is cooled 40 and theascorbic acid and remaining vitamins are added. The vitamin B component is ordinarily added toward the endof, the procedure. When it is desired to employ sodium carboxymethyl cellulose, guar gum or gelatin as a thickenenrhe thickener is first dissolved in glycerol and then this solution is added to the main batch. Certain materialsare conveniently added by first dissolving in dilute alkali andv then adding this solution to the main solution of the other materials in the polyol vehicle. Folic acidand thyroxin are examples of materials that are conveniently added in this fashion. When steroid materials are employed such as 'hydrocortisone, ethinylestradiol. and methyltestosterone, these materials are added by first dissolving in theminimum quantity of ethanol and then adding this solution to the polyol vehicle containing the other components. D-amphetamine sulfate can also be added in this fashion. A final stage of the preparation involves adjusting the pH to approximately 4-5. This can be done with a concentrated solution of citric acid in 70% aqueous sorbitol in the case of alkaline mixtures and withsodium bicarbonate in the case of acidic mixtures. I Sgecific examples of detailed preparations appear hereina er.

The stability of these preparations was demonstratedby a series of storage tests in which the compositions were stored at various temperatures and assayed at periodic intervals It was found that at room temperature and be-, low the preparations were highly stable for periods of at least six months. The stability of any particular preparation of course depends somewhat on theother components such as flavors, dyes, and other therapeutic agents contained therein in addition to the vitamin B ascorbic acid, and the iron. In some instances a loss in B activity of as much as 20% was observed in 6 months, but a loss e en ofthis size is neglibible compared to that ordinarily encountered in liquid compositions containing vitamin B ascorbic acid, and iron, and can be provided for by using an excess or over-age of the material beyond the dosage requirement under consideration. For comparison purposes, an aqueous solution containing in addition to ascorbic acid and'vitaminB sodium benzoate preservativewastested. This solution contained 1.67 mg. per m1. of ascorbic acid and 0.5 meg/ml. of vitamin B at the outset. In less than 2 weeks the vitamin B activityhad decreased to about .01 meg/ml. or by a factor of roughly 50. In the same period the ascorbic acid activity had decreased to 1.13 mgm./ml. corresponding to a loss of about one-third. Within two and one-half weeks the mixture had darkened and there was vitrtually no remaining vitamin B 5 or ascorbic acid activity. This is in startling contrast to the stability observed for the valuable compositions of the present invention which are given in detail hereinafter.

In the stability tests the vitamin B and ascorbic acid assays were carried out by standard assay procedures as described in the United States Pharmacopeia, vol. XV. Theperoxide modification was employed in those samples containing ferrous salts to eliminate interference from them. This modification is described in Vitamin Methods', volume I, Academic Press, New York (1950), by Paul Gyorgy. The vitamin B assay procedure was a microbiological method of the turbidimetric type employing Lactobacillus 'leichmannii as the test organism.

Various dyes, flavors, taste-masking substances, and sweetening agents can be employed in the above compositions to improve their .palatability and appeal. Caramel, lemon, peach, menthol, cocoanut, apricot, pineapple, quince and mint flavors have been found to be particularly suitable. Suitable sweetening agents include for example sodium saccharin. Dyes which have been approved for drug use that have been employed include,

D.& C red, No. 33; D & C red, No. 19; and D & C yellow, No. 10. V

In many instances it is desirable to employ a preservative in the composition to prevent the growth of microorganisms. Molds ,are particularly troublesome if preservatives are not employed. It is preferred to avoid the use of red-ox type preservatives such as sodium bisulfite or phenolic types. Preferredpreservatives include the parabens, sodium benzoate, sodium propionate and the quaternary ammonium types such as cetylpyridinium chloride and benzalkonium chloride. A small proportion of 'preservative is employed, generally less than about 5 mg./ml. V

The following examples are given to furtherillustrate the invention and are not considered to be limiting thereof in any way.

EXAMPLE I Hormone-tonic composition A liquid composition was prepared containing the following materi-als. The amounts indicated are those contained in .each, fluid ounce of the finished composition.

Sodium carboxymethyl cellulose (Hercules Powder Company) Type 70-LV mg 135 Ethanol V V l 3 -Thesodium c-arboxymethyl cellulose was dissolved in .75 the glycerolibyheatingto 110-115 C. underan atmos ring and heating at 70 C. were continued until these ma,-

terials were completely dissolved. The solution was then cooled to 2025 and the ascorbic acid, pyridoxine, thiamin and vitamin B added consecutively in that order with stirring after each addition until the materialhad completely dissolved. The liver fraction was then dispersed in the solution and :the formulation completed by adding the ethanolic hydrocortisone solution andthe carboxymethylcellulose-glycerine solution prepared above. The pH of this preparation was approxim-atelyS and the viscosity in the range 300-400 centipoises. The specific gravity was about 1.3. r r

In a storage test the vitamin B and ascorbic acid activities of this composition were without loss after 6 months at room temperature.

A similar composition was prepared in which flavors were added to increase the palatability of the product. The following flavors were added to the above formula: imitation butter carmel flavor (Alva, No. 3261), 0.03 ml.; and imitation floral mint (Alva, No. 3236), 0.003 ml.

Other preparations were prepared substituting prednisone and prednisolone for the hydrocortisone. In each of these formulations 3.0 mg. of the hormone was used.

EXAMPLE II Gariatric liquid tonic composition A composition was prepared containing the following materials in each fluid ounce.

The vehicle employed consisted of ethanol, 3 ml.; a 70% sorbitol solution on a weight basis, 20.2 ml.; glycerol, 6.8 ml.; carboxymethylcellulose (Hercules Powder Company, Type 70-LV), 135 mg.

These materials were compounded in much the same fashion as in Example I. Stock solutions were first prepared of the carboxymethylcellulose in the glycerol; of the ethinylestradiol, methyltestosterone and D-amphetamine sulfate in the ethanol; and of the thyroxine and folic acid in a small volume of 0.1 N sodium hydroxide. The ferrous gluconate was then dissolved in the sorbitol at 70 C., the solution cooled to room temperature, and the ascorbic acid added followed by the sodium hydroxide solution of the thyroxine and folic acid, the vitamin B and the liver fraction. The ethanolic solution of the ethinylestradiol, methyltestosterone, and- D- amphetamine sulfate was then added, followed by the the glycerol solution of carboxymethyl cellulose. As a final step the pH was adjusted to 4.0-4.2 with a concentrated solution of citric acid in 70% aqueous sorbitol.

The following flavors were added in some batches to increase the palatability of the composition; menthol, U.S.P. 0.017 g.; cocoanut flavor (Dolco No. 5245), 0.084 ml.; apricot aroma (Polak), 0.033 ml.; pineapple flavor (Busch No. 4253), 0.033 ml.

In storage tests, the vitamin B activity was found to decrease by about 20% in 6 months at 37 C. These 15 ceutically losses were compensated for by including a 20% excess" of these materials in the compositionover the normal requirement. i

' EXAMPLE III Pediatric hematinic liquid preparation A liquid composition containing the following materials in each fluid ounce was prepared.

Ascorbic acid Vitamin B mcg '12 Ferrous gluconate .g 0.518 70% aqueous sorbitol (weight basis) ml.. 30

The ferrous gluconate was dissolved in the 70% sorbitol at 70 C. with stirring. The mixture was then cooled to 25 and the ascorbic acid dissolved followed by the vitamin B The pH of the composition .was adjusted to 4.0 with sodium bicarbonate.

The following flavors can be added to the above composition to improve its palatability; imitation butter caramel flavor (Alva No. 3261), 0.03 ml.; imitation floral mint flavor (Alva No. 3236), 0.003 ml.; imitation lemon (Fritsche No. 23463), 0.0015 ml.

In storage tests at room temperature the vitamin B activity was found to be still stable and without change after 6 months. In 6 months at 37 C., the ascorbic acid activity decreased by about 25%. Considerably smaller decreases were observed at room temperature. This loss was generally provided for by including a 25% excess of ascorbic acid over the labeling statement.

What is claimed is:

1. A liquid pharmaceutical preparation comprising a vitamin B active substance, ascorbic acid, and a pharmaceutically acceptable form of iron in a vehicle comprising from about 50 to of a substance selected from the group consisting of an aliphatic hydrocarbon polyol containing at least five carbon atoms, and] the anhydro derivatives thereof, and up to about 30% of water, said vitamin B active substance, ascorbic acid, and iron being present in therapeutically effective amounts.

2. A liquid pharmaceutical preparation as claimed in claim 1 containing also a therapeutically effective amount of an anti-inflammatory steroid hormone.

3. A liquid pharmaceutical preparation as claimed in claim 1 containing also a therapeutically effective amount of an androgenic steroid hormone.

4. A liquid pharmaceutical preparation as claimed in claim 1 containing also a therapeutically effective amount of an estrogenic steroid hormone.

5. A liquid pharmaceutical preparation as claimed in claim 1 containing also a therapeutically effective amount of an anabolic steroid hormone.

6. A liquid pharmaceutical preparation comprising a vitamin B active substance, ascorbic acid, a pharmaceutically acceptable form of iron, and methyltestosterone in a vehicle comprising from about 50 to 75% of a substance selected from the group consisting of an aliphatic hydrocarbon polyol containing at least five carbon atoms and the anhydro derivatives thereof and up to about 30% of water, said vitamin B active substance, ascorbic acid, iron, and methyltestosterone being present in therapeutically effective amounts.

7. A liquid pharmaceutical preparation comprising a vitamin B active substance, ascorbic acid, a pharmaceutically acceptable form of iron, and ethinylestradiol in a vehicle comprising from about 50 to 75 of a substance selectedfrom the group consisting of an aliphatic hydrocarbon polyol containing at least five carbon atoms and the anhydro derivatives thereof and up to about 30% of water, said vitamin B active substance, ascorbic acid, iron, and ethinylestradiol being present in therapeutically effective amounts.

8. A liquid pharmaceutical preparation comprising a vitamin B active substance, ascorbic acid, a pharmaacceptable form of iron, and hydrocortisone iniawe cle .wmntisinaf m b u 1w 7 of a ub-n stanceselected from the,group consisting of an aliphatic hydrocarbon polyol containing at least five carbon atoms and the anhydro derivativesthereof. and up to about 30% of water, saidvitarnin B active substance, ascorbic acid, iron, and hydrocortisone'being present in therapeutically effective amounts.

9. A liquid pharmaceutical.preparationqcomprising a,

five carbon atoms and the anhydro. derivatives thereof and up to about 30% of water, said vitamin B active substance, ascorbicacid, iron, and prednisone being present' in therapeutically effective amounts.

10. A liquid pharmaceutical preparation comprising .a-vitamin B active substance, ascorbic acid, a pharmaceutically acceptable form of iron, and prednisolone in a vehiclecomprising from about 50 to 75% of a substancesselected i from thegrptiflconsisting of an aliphatic hydrocarbonpolyol containing at least five carbon atoms and-the, anhydro deriyatives thereof, and up tolabout ofwater,,saidvitaminiB active substance,ascorbic acid, iron, and; .prednisolone being presentin. therapeutically v effective amounts.

References Cited in the file of this patent UNITED STATES PATENTS OTHER REFERENCES 'Physicians.Desk'Reference, 9thed., 1954, pp. 420+ Stapert: J.A.P.A., Sci. ed., vol. 43, No. 2, February Bartilucci: I. of the Am. Pharm; Asso., Sci. ed., vol.

43,No. 3, March 1954, pp. 159-162.

Macek: J. of the. Am. Pharm. Asso., vol. 44, No..4,-

April 1955, p. 254.

Gulesich Feb. 4, 1 958 Newmark Feb. 11, 1958 wan-11, 

1. A LIQUID PHARMACEUTICAL PREPARATION COMPRISING A VITAMIN B12 ACTIVE SUBSTANCE, ASCORBIC ACID, AND A PHARMACEUTICALLY ACCEPTABLE FORM OF IRON IN A VEHICLE COMPRISING FROM ABOUT 50 TO 75% OF A SUBSTANCE SELECTED FROM THE GROUP CONSISTING OF AN ALIPHATIC HYDROCARBON POLYOL CONTAINING AT LEAST FIVE CARBON ATOMS, AND THE ANHYDRO DERIVATIVES THEREOF, AND UP TO ABOUT 30% OF WATER, SAID VITAMIN B12 ACTIVE SUBSTANCE, ASCORBIC ACID, AND IRON BEING PRESENT IN THERAPEUTICALLY EFFECTIVE AMOUNTS. 